Parkinson's Disease Research

Pathogenesis of Parkinson's Disease

The mechanism by which neurons are lost in PD is multifactorial and includes mitochondrial dysfunction, lysosomal dysregulation, α-synuclein aggregation and the formation of Lewy bodies. In sporadic, and some familial variants of PD, Lewy bodies are a characteristic feature of the disease. They are composed primarily of fibrillar α-synuclein-ubiquitin complexes that can not be directed to the proteasome for degradation and form aggregates in neurons. Early in the disease, Lewy bodies appear in the olfactory bulb and lower brain stem. As PD progresses and becomes symptomatic, Lewy body deposition and dopaminergic cell loss occurs in the substantia nigra pars compacta (SNpc). The precise pathogenic pathway in which Lewy bodies cause cell death is not known. A common theory is that Lewy bodies cause oxidative stress, mitochondrial dysfunction, excitotoxicity and inflammation. This leads to proteasomal dysfunction and improper protein metabolism, which promotes Lewy body formation. Neuronal dysfunction and apoptosis follows in the progressive neurodegenerative process of PD.

The locus ceruleus and substantia innominata are also involved in the degenerative process. Advanced PD exhibits prominent non-dopaminergic features and the serotonergic, noradrenergic, cholinergic and GABAergic pathways are compromised. Neurons are lost in the cortex, subcortex, brainstem and other peripheral autonomic sites. It is the loss of these non-dopaminergic pathways that is the major cause of the non-motor symptoms of PD, including cognitive decline and autonomic dysfunction.

Recently, the role of mitochondria in PD pathogenesis has become apparent. In the substantia nigra of PD brains the activity of mitochondrial complex I is significantly reduced. Function is not reduced within other PD brain areas. Furthermore, all environmental toxins identified so far that cause parkinsonism are mitochondrial inhibitors of complex I.

Both genetic and environmental factors are involved in the pathogenesis of PD. Mutations in several genes, including PRKN, PINK1, LRRK2, PARK7, SNCA and GBA, are linked to the development of PD. In rare cases of early-onset familial PD, mutations in a single gene are sufficient to drive pathology, with LRRK2 mutations being the most common cause of hereditary PD. Environmental factors that increase the risk of PD include living in a rural environment and increased exposure to herbicides and insecticides. Smoking and coffee consumption are known to reduce the risk of developing PD; α-synuclein gene mutation or multiplication can cause autosomal-dominant PD. Both genetic and environmental etiologies share a common pathogenic pathway.

Pharmacological Intervention

The motor symptoms that are characteristic of PD are mainly due to the loss of the nigrostriatal dopaminergic pathway. Pharmacological treatments of PD aim to improve symptoms by increasing dopaminergic stimulation or inhibiting cholinergic and/or glutamatergic stimulation. There are several ways to increase dopamine stimulation:

• Levodopa, a brain penetrant dopamine precursor, is metabolized to dopamine by dopa decarboxylase within the CNS
• Dopamine D₁, D₂ and D₃ receptor agonists can penetrate the blood-brain barrier (BBB) and activate pre- and post-synaptic dopamine receptors
• Monoamine oxidase B (MAO-B) inhibitors prevent the metabolism of dopamine and hence increase the synaptic half-life of dopamine and the amount of dopamine taken back up into the presynaptic terminal
• Catechol O-methyltransferase (COMT) inhibitors prevent the metabolism of levodopa to 3-O-methyldopa
• Increasing BDNF/TrkB signaling and expression contributes to an increase in dopamine signaling

The improved understanding of the etiology and pathogenesis of PD has enabled a range of compounds to be tested as putative drugs for neuroprotection. These target a number of different points in the cascade that cause dopaminergic cell dysfunction and death, and several have shown efficacy in vitro and in vivo. The implication is that those which are effective in slowing progression of dopamine cell death by interfering with biochemical pathways of damage will also be effective in slowing non-dopaminergic cell damage.

Resources for Parkinson's Disease Research

Blog Post: Regenerative Medicine - From Bench to Clinic

Regenerative medicine is the repair or replacement of damaged or diseased tissue to restore normal tissue function. This blog post discusses the development of a new cell therapy product derived from PSCs for regenerative medicine use in Parkinson's disease.

Read Now!